Hepatitis C virus (HCV) is a major health problem affecting approximately 200 million throughout the world. Although new therapies have improved the rates of sustained response, a large proportion of patients (~50%) fail to respond to antiviral treatment or develop significant drug toxicity, thus remaining at risk for disease progression. Thus, there is a pressing need for new preventative and therapeutic approaches, including vaccines. Understanding the viral evolutionary and immunologic events subsequent to HCV transmission, best assessed in the earliest stages of infection, is of direct relevance to vaccine design. However, acute HCV is often unrecognized because symptoms are usually mild or absent. We have established a large cohort of patients around the U.S. with acute HCV who we have followed longitudinally. In this proposal, we will examine mechanisms of CD8+ T cell escape, how functional attributes of these T cells influence the viral outcome of acute infection, and clone T cell receptors with optimal ability to recognize small amounts of peptide and mutant peptides. This will provide an important first step towards development of novel immunotherapeutic approaches. PUBLIC HEALTH RELEVANCE: Hepatitis C virus (HCV) is an enormous health problem affecting 3% of the population. There is a pressing need for to understand the host immune and viral events early after infection in order to develop new treatments, including vaccines.